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Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.

Publication ,  Journal Article
Baloni, P; Arnold, M; Buitrago, L; Nho, K; Moreno, H; Huynh, K; Brauner, B; Louie, G; Kueider-Paisley, A; Suhre, K; Saykin, AJ; Ekroos, K ...
Published in: Commun Biol
October 8, 2022

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.

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Published In

Commun Biol

DOI

EISSN

2399-3642

Publication Date

October 8, 2022

Volume

5

Issue

1

Start / End Page

1074

Location

England

Related Subject Headings

  • Sphingomyelins
  • Sphingolipids
  • Mice
  • Humans
  • Genome-Wide Association Study
  • Fingolimod Hydrochloride
  • Ceramides
  • Animals
  • Alzheimer Disease
  • 32 Biomedical and clinical sciences
 

Citation

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Baloni, P., Arnold, M., Buitrago, L., Nho, K., Moreno, H., Huynh, K., … Kaddurah-Daouk, R. (2022). Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease. Commun Biol, 5(1), 1074. https://doi.org/10.1038/s42003-022-04011-6
Baloni, Priyanka, Matthias Arnold, Luna Buitrago, Kwangsik Nho, Herman Moreno, Kevin Huynh, Barbara Brauner, et al. “Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.Commun Biol 5, no. 1 (October 8, 2022): 1074. https://doi.org/10.1038/s42003-022-04011-6.
Baloni P, Arnold M, Buitrago L, Nho K, Moreno H, Huynh K, et al. Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease. Commun Biol. 2022 Oct 8;5(1):1074.
Baloni, Priyanka, et al. “Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.Commun Biol, vol. 5, no. 1, Oct. 2022, p. 1074. Pubmed, doi:10.1038/s42003-022-04011-6.
Baloni P, Arnold M, Buitrago L, Nho K, Moreno H, Huynh K, Brauner B, Louie G, Kueider-Paisley A, Suhre K, Saykin AJ, Ekroos K, Meikle PJ, Hood L, Price ND, Alzheimer’s Disease Metabolomics Consortium, Doraiswamy PM, Funk CC, Hernández AI, Kastenmüller G, Baillie R, Han X, Kaddurah-Daouk R. Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease. Commun Biol. 2022 Oct 8;5(1):1074.

Published In

Commun Biol

DOI

EISSN

2399-3642

Publication Date

October 8, 2022

Volume

5

Issue

1

Start / End Page

1074

Location

England

Related Subject Headings

  • Sphingomyelins
  • Sphingolipids
  • Mice
  • Humans
  • Genome-Wide Association Study
  • Fingolimod Hydrochloride
  • Ceramides
  • Animals
  • Alzheimer Disease
  • 32 Biomedical and clinical sciences